TFAM Dependent Mitochondrial Fitness Limits CD8⁺ T Cell Immunopathology and Sustains Protective Immunity during Viral Pneumonia

Authors

Navaeiseddighi, Z., Guo, K., Hasan, S. S., Wang, Z., Mishra, R., Schmit, T., Ahsan, J., Moser, E. J., Hur, J., Yount, J. S., Mathur, R., Zhou, L., Khan, N.

Abstract

During respiratory virus infection, CD8 T cells kill infected cells and establish antigen-specific memory, but mechanisms regulating these functions remain incompletely understood. Here, we identify mitochondrial transcription factor A (TFAM)-dependent mitochondrial fitness as a regulator of CD8 T cell function during influenza infection. Human CD8 T cells exhibited an age-associated decline in TFAM expression and mitochondrial function. To model this physiologically relevant decline and determine its consequences for antiviral immunity, we generated CD8 T cell-specific TFAM-haploinsufficient mice. TFAM insufficiency disrupted mitochondrial integrity and bioenergetics and increased mitochondrial DNA and oxidative stress. During influenza infection, TFAM-insufficient CD8 T cells exhibited increased cytotoxic and inflammatory activity associated with lung immunopathology without improved viral control. This early phenotype was followed by loss of effector function, diminished antigen-specific responses, reduced protection following adoptive transfer, and impaired heterosubtypic recall immunity. Thus, TFAM-dependent mitochondrial fitness is a cell-intrinsic regulator that limits immunopathology while sustaining recall immunity.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 28 Sep 2026.

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